This invention relates to compounds that inhibit farnesyl-protein transferase and ras protein farnesylation, thereby making them useful as anti-cancer agents. The compounds are also useful in the treatment of diseases, other than cancer, associated with signal transduction pathways operating through ras and those associated with proteins other than ras that are also post-translationally modified by the enzyme farnesyl protein transferase. The compounds may also act as inhibitors of other prenyl transferases, and thus be effective in the treatment of diseases associated with other prenyl modifications of proteins.
The mammalian ras gene family comprises three genes, H-ras, K-ras and N-ras. The ras proteins are a family of GTP-binding and hydrolyzing proteins that regulate cell growth and differentiation. Overproduction of normal ras proteins or mutations that inhibit their GTPase activity can lead to uncontrolled cell division.
The transforming activity of ras is dependent on localization of the protein to plasma membranes. This membrane binding occurs via a series of post-translational modifications of the cytosolic Ras proteins. The first and mandatory step in this sequence of events is the farnesylation of these proteins. The reaction is catalyzed by the enzyme farnesyl protein transferase (FPT), and farnesyl pyrophosphate (FPP) serves as the farnesyl group donor in this reaction. The ras C-terminus contains a sequence motif termed a xe2x80x9cCys-Aaa1-Aaa2-Xaaxe2x80x9d box (CAAX box), wherein Cys is cysteine, Aaa is an aliphatic amino acid, and Xaa is a serine or methionine. Farnesylation occurs on the cysteinyl residue of the CAAX box (cys-186), thereby attaching the prenyl group on the protein via a thio-ether linkage.
In accordance with the present invention, compounds of the formulas I, II, III and IV 
their enantiomers, diastereomers, and pharmaceutically acceptable salts, prodrugs and solvates thereof inhibit farnesyl protein transferase which is an enzyme involved in ras oncogene expression. In formulas I-IV and throughout their specification, the above symbols are defined as follows:
m, n, r, s and t are 0 or 1;
p is 0, 1 or 2;
V, W and X are selected from the group consisting of oxygen, hydrogen, R1, R2 or R3;
Z and Y are selected from the group consisting of CHR9, SO2, SO3, CO, CO2, O, NR10, SO2NR11, CONR12, 
or Z may be absent;
R6, R7, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, and R38 are selected from the group consisting of hydrogen, lower alkyl, substituted alkyl, aryl, or substituted aryl;
R4, R5 are selected from the group consisting of hydrogen, halo, nitro, cyano and U-R23;
U is selected from the group consisting of sulfur, oxygen, NR24, CO, SO, SO2, CO2, NR25CO2, NR26CONR27, NR28SO2, NR29SO2NR30, SO2NR31, NR32CO, CONR33, PO2R34 and PO3R35 or U is absent;
R1, R2, and R3 are selected from the group consisting of hydrogen, alkyl, alkoxycarbonyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aralkyl, cycloalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, cyano, carboxy, carbamyl (e.g. CONH2) or substituted carbamyl further selected from CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl; R8 and R23 are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aralkyl, cycloalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo;
Any two of R1, R2, and R3 can be joined to form a cycloalkyl group;
R, S and T are selected from the group consisting of CH2, CO and CH(CH2)pQ wherein Q is NR36R37, OR38, or CN; and
A, B, C and D are carbon, oxygen, sulfur or nitrogen.
with the provisos that
1. When m is zero then V and W are not both oxygen or
2. W and X together can be oxygen only if Z is either absent, O, NR10, 
in formulas I and II, and V and X together can be oxygen only if Y is O, NR10, 
in formulas III and IV or
3. R23 may be hydrogen except when U is SO, SO2, NR25CO2 or NR28SO2, or
4. R8 may be hydrogen except when Z is SO2, CO2, or 
Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.
The term xe2x80x9calkylxe2x80x9d refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms. The expression xe2x80x9clower alkylxe2x80x9d refers to unsubstituted alkyl groups of 1 to 4 carbon atoms.
The term xe2x80x9csubstituted alkylxe2x80x9d refers to an alkyl group substituted by, for example, one to four substituents, such as, halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkoxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido, e.g. SO2NH2, substituted sulfonamido, nitro, cyano, carboxy, carbamyl, e.g. CONH2, substituted carbamyl e.g. CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclos, such as, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. Where noted above where the substituent is further substituted it will be with halogen, alkyl, alkoxy, aryl or aralkyl.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d refers to fluorine, chlorine, bromine and iodine.
The term xe2x80x9carylxe2x80x9d refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl and diphenyl groups, each of which may be substituted.
The term xe2x80x9caralkylxe2x80x9d refers to an aryl group bonded directly through an alkyl group, such as benzyl.
The term xe2x80x9csubstituted arylxe2x80x9d refers to an aryl group substituted by, for example, one to four substituents such as alkyl, substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, cycloalkylamino, heterocycloamino, dialkylamino, alkanoylamino, thiol, alkylthio, cycloalkylthio, heterocyclothio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, alkysulfonyl, sulfonamido, aryloxy and the like. The substituent may be further substituted by halo, hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl.
The term xe2x80x9calkenylxe2x80x9d refers to straight or branched chain hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, and most preferably 2 to 8 carbon atoms, having one to four double bonds.
The term xe2x80x9csubstituted alkenylxe2x80x9d refers to an alkenyl group substituted by, for example, one to two substituents, such as, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino and heterocyclo, e.g. indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
The term xe2x80x9calkynylxe2x80x9d refers to straight or branched chain hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, and most preferably 2 to 8 carbon atoms, having one to four triple bonds.
The term xe2x80x9csubstituted alkynylxe2x80x9d refers to an alkynyl group substituted by, for example, a substituent, such as, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino and heterocyclo, e.g. imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
The term xe2x80x9ccycloalkylxe2x80x9d refers to a optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocylic ring. Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl, cyclodecyl, cyclododecyl, and adamantyl. Exemplary substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
The terms xe2x80x9cheterocyclexe2x80x9d, xe2x80x9cheterocyclicxe2x80x9d and xe2x80x9cheterocycloxe2x80x9d refer to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom.
Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydrothiopyranyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, tetrahydrothiopyranylsulfone, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1, 1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl, and triazolyl, and the like.
Exemplary bicyclic hetrocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl, and the like.
Exemplary substituents include one or more alkyl groups as described above or one or more groups described above as alkyl substituents. Also included are smaller heterocyclos, such as, epoxides and aziridines.
The term xe2x80x9cheteroatomsxe2x80x9d shall include oxygen, sulfur and nitrogen.
The xe2x80x9cABCxe2x80x9d ring and the xe2x80x9cABCDxe2x80x9d fused ring to the diazepine ring may be monocyclic or bicyclic, e.g. napthyl or quinolyl in nature.
The compounds of formulas I-IV may form salts which are also within the scope of this invention. Pharmaceutically acceptable (i.e. non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolating or purifying the compounds of this invention.
The compounds of formulas I-IV may form salts with alkali metals such. as sodium, potassium and lithium, with alkaline earth metals such as calcium and magnesium, with organic bases such as dicyclohexylamine, tributylamine, pyridine and amino acids such as arginine, lysine and the like. Such salts may be obtained, for example, by exchanging the carboxylic acid protons, if they contain a carboxylic acid, in compounds I-IV with the desired ion in a medium in which the salt precipitates or in an aqueous medium followed by evaporation. Other salts can be formed as known to those skilled in the art.
The compounds for formulas I-IV may form salts with a variety of organic and inorganic acids. Such salts include those formed with hydrogen chloride, hydroxy methane sulfonic acid, hydrogen bromide, methanesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid and various others (e.g., nitrates, phosphates, borates, tartrates, citrates, succinates, benzoates, ascorbates, salicylates and the like).
Such salts may be formed by reacting compounds I-IV in an equivalent amount of the acid in a medium in which the salt precipitates or in an aqueous medium followed by evaporation.
In addition, zwitterions (xe2x80x9cinner saltsxe2x80x9d) may be formed.
Compounds of the formulas I-IV may also have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., the compound for formulas I-IV) is a prodrug within the scope and spirit of the invention.
For example compounds of the formulas I-IV may be a carboxylate ester moiety. The carboxylate ester may be conveniently formed by esterifying any of the carboxylic acid functionalities found on the disclosed ring structure(s).
Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:
a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and, Methods in Enzymology, Vol.42, p. 309-396, edited by K. Widder, et al. (Acamedic Press, 1985);
b) A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H. Bundgaard, Chapter 5, xe2x80x9cDesign and Application of Prodrugs,xe2x80x9d by H. Bundgaard, p. 113-191 (1991);
c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);
d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and
e) N. Kakeya, et al., Chem Phar Bull, 32, 692 (1984).
It should further be understood that solvates (e.g., hydrates) of the .compounds of formulas I-IV are also with the scope of the present invention. Methods of solvation are generally known in the art.
Preferred Moieties
For compounds of the present invention, the following moieties are preferred:
Compounds of Formulas I, II, III and IV wherein m is zero.
More preferred are compounds of Formula I, II, III and IV wherein m is zero and n is one.
Most preferred are compounds of formula I wherein m, r, s and t are zero, n is one and xe2x80x9cABCDxe2x80x9d is a carbocyclic ring, e.g., benzo.
Use and Utility
The compounds of formulas I-IV are inhibitors of S-farnesyl protein transferase. They are thus useful in the treatment of a variety of cancers, including (but not limited to) the following;
carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, ovary, prostate, testes, pancreas, esophagus, stomach, gall bladder, cervix, thyroid and skin, including squamous cell carcinoma;
hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, and Burketts lymphoma;
hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia;
tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma, and schwannomas;
tumors of mesenchymal origin, including fibrosarcoma, rhabdomyoscarcoma, and osteosarcoma;
other tumors, including melanoma, xenoderma pigmentosum, keratoactanthoma, seminoma, thyroid follicular cancer and teratocarcinoma.
The compounds of formulas I-IV are especially useful in treatment of tumors having a high incidence of ras involvement, such as colon, lung, and pancreatic tumors and in tumors in which a prenyl transferase contributes to tumor maintenance, tumor growth or tumor development. By the administration of a composition having one (or a combination) of the compounds of this invention, development of tumors in a mammalian host is reduced, or tumor burden is reduced, or tumor regression is produced.
Compounds of formulas I-IV may also inhibit tumor angiogenesis, thereby affecting the growth of tumors. Such anti-angiogenesis properties of the compounds of formulas I-IV may also be useful in the treatment of certain forms of blindness related to retinal vascularization.
Compounds of formulas I-IV may also be useful in the treatment of diseases other than cancer that may be associated with signal transduction pathways operating through ras, e.g., neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, polycystic kidney disease and endotoxic shock. Compounds I-IV may be useful as anti-fungal agents.
Compounds of formula I-IV may induce or inhibit apoptosis, a physiological cell death process critical for normal development and homeostasis. Alterations of apoptotic pathways contribute to the pathogenesis of a variety of human diseases. Compounds of formula I-IV, as modulators of apoptosis, will be useful in the treatment of a variety of human diseases with aberrations in apoptosis including cancer (particularly, but not limited to follicular lymphomas, carcinomas with p53 mutations, hormone dependent tumors of the breast, prostrate and ovary, and precancerous lesions such as familial adenomatous polyposis), viral infections (including but not limited to herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), autoimmune diseases (including but not limited to systemic lupus erythematosus, immune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowl diseases and autoimmune diabetes mellitus), neurodegenerative disorders (including but not limited to Alzheimer""s disease, AIDS-related dementia, Parkinson""s disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), AIDS, myelodysplastic syndromes, aplastic anemia, ischemic injury associated myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol induced liver diseases, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases, and cancer pain.
Compounds of formulas I-IV may also be useful in the treatment of diseases associated with farnesyl transferase substrates other than ras (e.g., nuclear lamins, transducin, rhodopsin kinase, cGMP phosphodiesterase, TC21, phosphorylase kinase, Rap2, RhoB, RhoE, PRL1) that are also post-translationally modified by the enzyme farnesyl protein transferase.
Compounds of formulas I-IV may also act as inhibitors of other prenyl transferases (e.g., geranylgeranyl transferase I and II), and thus be effective in the treatment of diseases associated with other prenyl modifications (e.g., geranylgeranylation) of proteins (e.g. the rap, rab, rac and rho gene products and the like). For example, they may find use as drugs against Hepatitis delta virus (HDV) infections, as suggested by the recent finding that geranylgeranylation of the large isoform of the delta antigen of HDV is a requirement for productive viral infection [J. S. Glen, et al., Science, 2, 1331 (1992)].
The compounds of this invention may also be useful in combination with known anti-cancer and cytotoxic agents and treatments, including radiation. If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within its approved dosage range. Compounds of formulas I-IV may be used sequentially with known anticancer or cytotoxic agents and treatment, including radiation when a combination formulation is inappropriate.
Farnesyl transferase assays were performed as described in V. Manne et al., Drug Development Research, 34, 121-137, (1995). The compounds of Examples 1-431 inhibited farnesyl transferase with IC 50 values between 0.1 nM and 100 uM.
The compounds of this invention may be formulated with a pharmaceutical vehicle or diluent for oral, intravenous, intraperitoneal, subcutaneous, intraabdominal, intramuscular, rectal, vaginal or topical administration. Oral administration may involve the use of slow release formulations, such as biodegradable polymers or prodrugs. The pharmaceutical composition can be formulated in a classical manner using solid or liquid vehicles, diluents and additives appropriate to the desired mode of administration. Orally, the compounds can be administered in the form of tablets, capsules, granules, powders and the like. The compounds may be administered in a dosage range of about 0.05 to 200 mg/kg/day, preferably less than 100 mg/kg/day, in a single dose or in 2 to 4 divided doses.
Process of Preparation 
Step 1
The first step is accomplished by the reaction of the anthranilic acid with a phosgene equivalent, such as, phosgene or triphosgene in a mixed aqueous/organic solvent at room temperature to 50xc2x0 C. range.
Step 2
The product is reacted with an amino acid hydrochloride salt or an amino acid ester hydrochloride salt in pyridine at an elevated temperature with reflux as preferred. Step 2 of Scheme 1 may be performed in 2 steps, wherein the isatoic anhydride is condensed with an amino acid in an organic solvent solvent such as pyridine at from 0xc2x0 C. to reflux and the resulting anthraniloylamino acid is cyclized under standard amide bond forming conditions, e.g., using HOBt/carbodiimide in an organic solvent such as DMF at from 0xc2x0 C. to room temperature. Some compounds 1 of Scheme 1 wherein R1=halogen are not commercially available. Such compounds 3, 4 or 5 of Scheme 1 wherein R1=halogen can be prepared from compounds 3, 4 or 5 of Scheme 1 wherein R1=hydrogen by halogenation, for example by reaction with bromine in an organic solvent such as acetic acid at from 0xc2x0 C. to room temperature. The compound 3 wherein R1 is aryl or heteroaryl can be prepared from the compound 3 wherein R1 is bromo, iodo or trifluoromethanesulfonyloxy by a palladium coupling of an aryl or heteroaryl metaloid derivative such as phenylboronic acid in a mixed aqueous/organic solvent, e.g. THF/DMF/water, in the presence of a base, e.g. sodium carbonate, at from room temperature to 90xc2x0 C. (Alternatively, the compound of Scheme 1 where R1=aryl or heteroaryl is also prepared from a compound 2 of Scheme 5 where R1 is bromo, iodo or trifluoromethanesulfonyloxy by reaction with an aryl metaloid derivative such as phenylboronic acid or tributyl-stannylpyridine in a deoxygenated organic (e.g., THF) or mixed aqueous/organic solvent system such as aqueous NaHCO3/toluene in the presence of a palladium catalyst such as tetrakis(triphenylphosphine) palladium at from room temperature to 100xc2x0 C. Deprotection then affords the target compound.) Alternatively such Suzuki or Stille couplings can be performed on a compound 1 of Scheme 1, or on a compound 4 of Scheme 1, or on a compound 5 of Scheme 1 where the unacylated benzodiazepine nitrogen may be optionally protected, e.g., with a trifluoroacetyl group, and subsequently deprotected. The compound 3 wherein R1 is alkoxy is prepared by alkylation of the corresponding hydroxy compound under standard conditions. The compound 3 wherein R1 is alkylaminoalkylaryl is prepared from the compound 3 wherein R1 is an aryl aldehyde by reductive amination under standard conditions.
Step 3
Thereafter the compound 3 is reacted with a reducing agent, such as lithium aluminum hydride or borane in an inert organic solvent, such as, tetrahydrofuran at from room temperature to reflux. If R1 or R2 contain functional groups, e.g., CO2R, which are reduced by, e.g. lithium aluminum hydride, to, e.g. CH2OH, these groups will also be reduced by step 3. The compound 4 or 6 wherein R1 is CN can be prepared from the compound 4 or 6 wherein R1=halogen by displacement with CuCN in an inert solvent such as NMP at elevated temperature. The compound 4 wherein R1 is CO2H can be prepared from the compound 4 wherein R1=CN by hydrolysis, e.g. by heating with aqueous sodium hydroxide in a suitable solvent such as ethanol at 100xc2x0 C.; thereafter the product wherein R1=CONR5R6 may be prepared by standard amide bond coupling conditions.
Step 4
Thereafter the product is acylated or sulfonylated under standard conditions at from xe2x88x9278xc2x0 C. to room temperature (e.g., by reaction with an acid halide R3COX wherein X is Cl or Br in an inert organic solvent, e.g. acetonitrile, or in a mixed aqueous/organic solvent e.g. NaOH/dichloroethane; by reaction with an O-phenyl ester in an inert organic solvent, e.g. acetonitrile; by reaction with a carboxylic acid in the presence of a coupling agent, e.g. DCC or EDC in an inert organic solvent, such as DMF; by reaction with a haloformate such as ethyl, isopropyl or 4-nitrophenylchloroformate in an inert solvent such as dichloromethane at from 0xc2x0 C. to room temperature in the presence of an optional base such as diisopropylethylamine to form carbamates, some of which, e.g. 4-nitrophenyl-carbamate, are reacted with an amine, e.g. N,N,Nxe2x80x2-trimethylethylenediamine, at from room temperature to 110xc2x0 C. to form ureas; by reaction with a carboxylic or sulfonyl anhydride such as succinic anhydride or trifluoromethanesulfonyl anhydride in an inert solvent such as ethyl acetate, dichloromethane or pyridine at from 0xc2x0 C. to room temperature in the presence of an optional base such as diisopropylethylamine; by reaction with an isocyanate in an inert solvent such as THF; by reaction with a carbamyl chloride R5R6NCOX wherein X is Cl or Br in an inert solvent such as acetonitrile in the presence of a base such as diisopropylethylamine/dimethyl-aminopyridine; by reaction with a sulfonyl halide R3SO2X wherein X is Cl or Br in a mixed aqueous/organic solvent e.g. NaOH/CH2Cl2; by reaction with a halosulfonate ROSO2X wherein X is Cl or Br in an inert solvent such as CH2Cl2; by reaction with a sulfamoyl chloride R5R6NSO2X wherein X is Cl or Br in an inert solvent such as acetonitrile in the presence of a base such as diisopropylethylamine/dimethyl-aminopyridine; by reaction with an N-cyano-thiourea NH(CN)C(S)NR5R6 in the presence of a coupling reagent such as a carbodiimide in an inert solvent such as DMF at about room temperature; by reaction with a cyanocarbonimidate such as diphenylcyanocarbonimidate in a suitable solvent such as DMF in the presence of a base such as diisopropylethylamine at from room temperature to 80xc2x0 C., followed by reaction with an amine such as methylamine at about room temperature). The compound 5 wherein R1 is halogen, e.g. bromine, may be prepared from the compound 5 wherein R1=H by reaction with a halogenating agent, e.g. tetrabutylammonium perbromide, in an inert solvent such as chloroform at about room temperature. Where R1 or R2 contain CH2OH, the acylation may be performed in such a manner as to obtain the diamide ester; the ester may then be cleaved, e.g., by sodium methoxide in methanol and the resulting alcohol oxidized to an acid, e.g., by Jones reagent; the N1 amide may then be cleaved, e.g., by KOH in aqueous methanol at reflux, and the acid may be coupled with amines under standard peptide coupling conditions to form compounds 5 of Scheme 1 where R1 or R2 is a carboxamide. Where R1 or R2 contain CH2O-Prot, the protecting group may be removed, e.g., Boc by treatment with an acid such as TFA in an inert solvent such as dichloromethane to form a compound 5 or 6 where R1 or R2 is CH2OH. The compound 5 where R1 or R2 is aryloxyalkyl is prepared from a compound 5 where R1 or R2 is CH2OH by transformation of the alcohol into a leaving group such as a triflate. e.g., by treatment with triflic anhydride in dichloromethane at xe2x88x9240xc2x0 C., and displacement with an aralkoxide salt, e.g., in dichloromethane at from xe2x88x9240xc2x0 C. to room temperature. The compound 5 where R1 or R2 is CH2NH2 is prepared from a compound 5 where R1 or R2 is CH2OH by transformation of the alcohol into a leaving group such as a triflate. e.g., by treatment with triflic anhydride in dichloromethane at xe2x88x9240xc2x0 C., and displacement with ammonia, e.g., in dichloromethane at from xe2x88x9240xc2x0 C. to room temperature. The amine may be subsequently coupled to carboxylic acids by standard amide bond coupling conditions. Where the compound 5 is sulfonylated with a beta-haloalkylsulfonyl halide, the halide may then be eliminated by a base such as diisopropylethylamine and then nucleophiles such as dimethylamine or sodium imidazolate may be added to the resulting unsaturated sulfonamide by treatment in an organic solvent such as THF or dichloromethane at from room temperature to reflux. Where the compound 5 is acylated or sulfonylated with an acylating or sulfonylating agent which contains a leaving group, e.g. chloride or bromide, that leaving group may be displaced by nucleophiles, e.g., by amines such as dimethylamine or N-methylpiperazine in an inert solvent such as THF or DMF in the presence of an optional base such as diisopropylethylamine at from 0xc2x0 C. to 110xc2x0 C.
Step 5
Thereafter the various products can undergo reductive alkylation in the presence of an acid e.g. acetic acid, a reducing agent e.g. NaBH(OAc)3 in an inert organic solvent e.g. dichloroethane at about room temperature. Reductive alkylation may also be performed using hydrogen and a catalyst such as Pd on carbon in a solvent such as ethanol in the presence of an acid such as acetic acid at about room temperature.
Thereafter, the compound of Scheme 1 where R1=halogen can be metallated and quenched , e.g., with water to form the compound where R1=H or with carbon dioxide to form the compound where R1=CO2H; this acid may be coupled with amines under standard peptide coupling conditions to form compounds of Scheme 1 where R1 is a carboxamide. The compound of Scheme 1 wherein R1=halogen can be metallated and quenched with a ketone such as cyclohexanone followed by reduction of the alcohol with for example trifluoroacetic acid/sodium borohydride to form the compound where R1=e.g., cyclohexyl. The compound of Scheme 1 in which the imidazole contains a 2-dimethylaminomethyl group can be prepared by standard Mannich conditions. The compound of Scheme 1 in which R1=OH can be prepared from the compound of Scheme 1 in which R1=OMe by dealkylation, e.g., by treatment with BBr3. The compound of Scheme 1 in which R1=arylOalkyl can be prepared from the compound of Scheme 1 in which R1=HOalkyl by Mitsunobu reaction with the aryl alcohol. The compound of Scheme 1 in which R3=aryl-NH2 or heteroaryl-NH2 can be prepared from the compound of Scheme 1 in which R3=aryl-NO2 or heteroaryl-NO2 by reduction (e.g., SnCl2) under standard conditions. The product can be further acylated, sulfonylated or reductively aminated under standard conditions. 
Step 1
In Scheme 2 the starting material is reduced via hydrogenation in the presence of platinum oxide. The reaction is carried out in the presence of an alcohol e.g. ethanol at about room temperature.
Step 2 and 3
Thereafter the product is monoacylated or monosulfonylated under standard conditions at from xe2x88x9278xc2x0 C. to room temperature (e.g., by reaction with an acid halide R2COX wherein X is Cl or Br in an inert organic solvent, e.g. acetonitrile, or in a mixed aqueous/organic solvent e.g. NaOH/methylene chloride; or by reaction with a sulfonyl halide R3SO2X wherein X is Cl or Br in an organic solvent e.g. CH2Cl2 in the presence of a base such as triethylamine). Thereafter the product undergoes a reductive alkylation as outlined in the last step of Scheme 1. 
In Scheme 3, compound 1 is suitably protected by, for example, a tertbutoxycarbonyl group. The reaction is carried out in an inert organic solvent e.g. THF at about room temperature. The compound 2 where R1 is an amine may be selectively acylated, e.g., by reaction with isobutylchloroformate in an inert solvent such as methylene chloride in the presence of a base such as diisopropylethylamine at about room temperature. The compound 2 where an R1 is R5CONH and another R1 is Br is prepared from the compound where an R1 is R5CONH by bromination, e.g. with tetrabutylammonium tribromide in an inert solvent such as chloroform at about room temperature. Thereafter the compound 2 is reacted with a compound of the formula R3COCl in the presence of pyridine in an inert organic solvent, such as, dichloroethane at from about 0xc2x0 C. to room temperature. Thereafter the compound 3 is deprotected by reaction with, for example, trifluoroacetic acid in an inert organic solvent, such as, dichloroethane at about room temperature. Thereafter the compound 4 undergoes reductive alkylation following the steps outlined in Scheme 1. 
In Scheme 4 the compound 1 is reacted with a compound of the formula R2COCO2Me in the presence of an organic acid e.g. acetic acid, a reducing agent, such as, NaCNBH3 or NaBH(OAc)3 in an inert organic solvent, such as, dichloroethane at about room temperature. The intermediate is thereafter deprotected by reaction with, for example, trifluoroacetic acid in an inert organic solvent, e.g. CH2Cl2 at about room temperature, and cyclized by heating, e.g., at 60xc2x0 C. to form the compound 2. Thereafter the compound 2 undergoes reductive alkylation as outlined in Scheme 1 to form a compound 3. The compound 3 may be reduced, e.g. with lithium aluminum hydride, to a compound 4, which may be reacted to form a compound 6 as described in Scheme 12. Alternatively, the compound 2 is reduced to the compound 5, as outlined in Scheme 1, and the compound 5 is reacted as outlined in Scheme 1. 
In Scheme 5 the compound 1 is protected by reaction with, for example, triphenylmethyl chloride or Boc anhydride in an inert organic solvent e.g. acetonitrile or tetrahydrofuran, from about room temperature to reflux. Thereafter the compound 2 is reacted with a compound of the formula R4-L wherein L is a leaving group such as triflate, in the presence of a base such as diisopropylethylamine in an inert organic solvent such as tetrahydrofuran at from about xe2x88x9278xc2x0 C. to room temperature. R4 may contain a protecting group, e.g., phthalimide, removable by e.g. hydrazine. The reaction of Scheme 5 with R4-L may also be performed on a compound 1 to directly produce a compound 3 without protection/deprotection. 
In Scheme 6, a cyanoacetylamino acid is reacted with a dithianediol in a suitable solvent such as ethanol in the presence of bases such as piperidine and triethylamine at from room temperature to 80xc2x0 C. The intermediate is then cyclized in a suitable solvent such as pyridine in the presence of a catalyst such as pyridinium hydrochloride at an elevated temperature such as 130xc2x0 C. Thereafter the compound is reacted as described in Scheme 1. 
The compound 1 of Scheme 7 undergoes reduction (e.g., Fe, SnCl2, or TiCl3) under standard conditions. The compound 2 is acylated or sulfonylated under standard conditions (e.g., by reaction with an anhydride and an acylation catalyst such as DMAP, by reaction with an acid halide, by reaction with a carboxylic acid under standard peptide coupling conditions, by reaction with an alkoxycarbonylchloride, by reaction with an isocyanate, by reaction with a sulfonyl halide or by reaction with a sulfamyl chloride) or reductively alkylated under standard conditions (e.g., by reaction with an aldehyde and a reducing agent such as NaCNBH3 or Na(OAc)3BH in an organic solvent such as dichloroethane or DMF in the presence of an acid such as acetic acid at from 0xc2x0 C. to room temperature). 
The compound 1 of Scheme 8 is reacted with an ethylenediamine and the product 2 undergoes reduction, selective acylation or sulfonylation and reductive alkylation to produce a compound 3 as outlined in Scheme 1. Alternatively, Step 1 of Scheme 8 may be performed in 2 steps, wherein the ethylenediamine is condensed with the halogenated heterocycle either neat or in an organic solvent at elevated temperature and the resulting amino acid is cyclized under standard amide bond forming conditions, e.g., using HOBt/carbodiimide in an organic solvent such as DMF or pyridine at from 0xc2x0 C. to room temperature. Some compounds 1 of Scheme 8 wherein R1=halogen are not commercially available. Such compound 2 of Scheme 8 wherein R1=halogen can be prepared from compound 2 of Scheme 8 wherein R1=hydrogen by halogenation, for example by reaction with bromine in an organic solvent such as acetic acid at from 0xc2x0 C. to room temperature. The compound 2 wherein R1=aryl or heteroaryl can be prepared from the compound 2 wherein R1 is halogen or trifluoromethanesulfonyloxy by standard Suzuki or Stille couplings as described for Step 2 of Scheme 1. Thereafter the product undergoes reduction, acylation or sulfonylation, and reductive alkylation as outlined in Scheme 1. Compound 2 of Scheme 8 may itself undergo reductive alkylation with an imidazole containing aldehyde as outlined in Scheme 1 to afford a target compound. 
Some imidazole aldehydes are prepared as follows. An imidazole containing aldehyde undergoes a Wittig reaction with a compound of the formula triethylphosphonoacetate in the presence of a base, such as, sodium hydride in an inert organic solvent, such as dimethoxyethane, at from about 0xc2x0 C. to room temperature. The product is hydrogenated in an alcohol e.g. ethanol at about room temperature and reduced by reaction with DIBAL in for example dichloroethane at about xe2x88x9278xc2x0 C. Alternatively, some aminoalkyl containing imidazolylalkanols, prepared by known methods (e.g., Buschauer, et. al., Arch. Pharm., 315, 563, (1982)) are protected with a Boc group as in Scheme 3, step 1, and undergo an oxidation, e.g. under Swern conditions. 
In Scheme 10 the starting material is reacted with allyl magnesium bromide in the presence of lithium hexamethyldisilazide in an inert solvent e.g. THF at from about xe2x88x9278xc2x0 C. to room temperature. The product is protected, e.g. with a Teoc group, in an aqueous/organic solvent e.g. aqueous dioxane at about room temperature. The product is oxidized by reaction with e.g. OsO4/NalO4 in aqueous dioxane at about room temperature. Thereafter the product undergoes reductive alkylation as in Scheme 1 and thereafter the product is deprotected with tetrabutylammonium fluoride at from room temperture to 50xc2x0 C. in THF. 
In Scheme 11 the starting material is reduced with e.g. lithium aluminum hydride in an inert organic solvent e.g. ethylene glycol dimethyl ether at from about 0xc2x0 C. to reflux. 
In step 1 of Scheme 12, a monoprotected benzodiazepine such as that described in Scheme 3 is coupled with an optionally protected imidazole-containing carboxylic acid using standard amide bond formation methods such as isobutylchloroformate in an organic solvent such as THF at from xe2x88x9230xc2x0 C. to room temperature. In step 2 of Scheme 12, the resulting amide is reduced with for example borane in an organic solvent such as THF at from room temperature to reflux. A compound 3 of Scheme 12 may contain a nitro group which may be reduced, e.g., by TiC3, to an amine, which may then be acylated or sulfonylated as described in Scheme 7. In step 3 of Scheme 12, the amine protecting group is removed (e.g., Boc by an acid such as TFA in an organic solvent such as methylene chloride). In step 4 of Scheme 12, the resulting compound is reacted under standard conditions with a variety of active acylating or sulfonylating agents to form the claimed compound, such as acids under carbodiimide conditions or acid chlorides to form amides; carbonates or chloroformates to form carbamates; carbamyl chlorides or isocyanates to form ureas; sulfonyl chlorides to form sulfonamides; halosulfonates to form sulfamates; sulfamoyl chlorides to form sulfonylureas. In step 4 of Scheme 12, the resulting compound is alternatively reacted under standard reductive amination conditions with aldehydes as described in Step 5 of Scheme 1 to form the claimed compounds. If the imidazole is optionally protected, it is then deprotected. 
In step 1 of Scheme 13, a monoprotected benzodiazepine such as that described in Scheme 3 is reductively alkylated with an imidazole-containing aldehyde and a reducing agent such as NaCNBH3 or Na(OAc)3BH in an organic solvent such as dichloroethane or DMF in the presence of an acid such as acetic acid at from 0xc2x0 C. to room temperature. Thereafter, the product is reacted as described in Scheme 12. The product 2 may be attached to a solid support, e.g. polystyrene resin, and the reactions of Scheme 1 may be performed on resin-bound material. Removal from the support, e.g. by treatment with an acid such as trifluoroacetic acid in the presence of a scavenger such as triethylsilane at about room temperature, then provides the compound 6 of Scheme 1. 
In step 1 of Scheme 14, an aminobenzoic acid is reductively aminated with an N-protected aminoaldehyde under standard conditions, e.g. by reaction with a hydride reagent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent such as methylene chloride or methanol in the presence of an acid such as acetic acid at from 0xc2x0 C. to about room temperature. The product is deprotected by, e.g., removal of Boc by treatment with an acid such as TFA or HCl in the presence of an optional scavenger such as dimethylsulfide in a suitable solvent such as methylene chloride or dioxane at about room temperature or removal of Fmoc by treatment with a secondary amine in tetrahydrofuran at about room temperature. Thereafter, the product is cyclized under standard amide bond forming conditions, such as by treatment with diphenylphosphoryl azide in an organic solvent such as DMF. Thereafter, the product is reacted as described in Scheme 1. 
In step 1 of Scheme 15, a benzodiazepinedione is sulfonylated with chlorosulfonic acid and the resulting sulfonyl chloride is condensed with an amine. Thereafter, the product is reacted as described in Scheme 1. 
In step 1 of Scheme 16, a benzodiazepine of Scheme 1 can be doubly reductively alkylated with an imidazole containing aldehyde and a reducing agent such as NaCNBH3 or Na(OAc)3BH in an organic solvent such as dichloroethane or DMF in the presence of an acid such as acetic acid at from 0xc2x0 C. to room temperature. 
In step 1 of Scheme 17, a benzodiazepine of Scheme 1 can be reacted with R3-L in an inert solvent such as DMF, THF or methylene chloride in the presence of a base such as diisopropylethylamine or potassium carbonate at from 0xc2x0 C. to 100xc2x0 C., where L is a leaving group such as chloride, bromide, mesylate, tosylate or triflate and R3 is a substituted alkyl group, a substituted aryl group or a substituted heterocylic group. Thereafter, the product is reacted as described in Scheme 1. 
Step 1
The first step accomplished by the reaction of a pyridine containing a protected amino group and a methyl group with an oxidizing agent, such as hydrogen peroxide in a suitable solvent such as aqueous acetic acid or trifluoroacetic acid at from room temperature to 75xc2x0 C.
Step 2
The product is acylated with an acylating agent such as acetic anhydride and rearranged by heating from room temperature to 90xc2x0 C. in a suitable solvent such as acetic acid.
Step 3
The product is deacylated, e.g., with aqueous NaOH at from room temperature to 50xc2x0 C. and oxidized to the aldehyde with e.g. MnO2 in a suitable solvent such as tetrahydrofuran at about room temperature.
Step 4
The product is reductively aminated with an aminoacid ester under standard conditions, e.g., by hydrogenation in an inert solvent such as methanol or by reaction with a hydride reagent such as sodium triacetoxyborohydride in a suitable solvent such as methylene chloride/acetic acid at about room temperature.
Step 5
The product is deprotected and cyclized with, e.g. treatment with polyphosphoric acid at from room temperature to 100xc2x0 C.
Step 6
The product is sulfonylated as described for Step 4 of Scheme 1.
Step 7
The product is reduced as described for Step 3 of Scheme 1. Thereafter, the product is reacted as described in Step 5 of Scheme 1; 
The first step is accomplished by the reaction of a pyrimidine containing a halide and a carboxylic acid group with an optionally monoprotected diamine in a suitable solvent such as water in the presence of a catalyst such as CuSO4 at from room temperature to 100xc2x0 C. Thereafter, the product is reacted as described in Scheme 14. 
Step 1
The first step is accomplished by reductive amination of a nitrobenzaldehyde with an amino acid ester under standard conditions, e.g., by reaction with a hydride reagent such as sodium triacetoxyborohydride in a suitable solvent such as methylene chloride/acetic acid at about room temperature.
Step 2
The product is sulfonylated as described for Step 4 of Scheme 1.
Step 3
The nitro group of the product is reduced to an amine under standard conditions, such as reaction with SnCl2 or TiCl3. The compound where R1=Br may be prepared from the compound where R1=H by bromination, such as reaction with tetrabutylammonium perbromide in an inert solvent such as chloroform at about room temperature.
Step 4
The product is cyclized by heating with CuCN in an inert solvent such as N-methylpyrrolidinone at from room temperature to 195xc2x0 C. The compound where R1=CN is prepared from the compound where R1=halogen under the same conditions.
Step 5
The product is alkylated with an optionally protected imidazolylalkanol under Mitsunobu conditions. Thereafter, the product is optionally reacted as described in Scheme 5. 
A compound 3 of Scheme 1 may be selectively reduced, e.g. by reaction with a reducing agent, such as borane in an inert organic solvent, such as, tetrahydrofuran at about room temperature. Thereafter, the product (2) is reductively aminated as described in Scheme 1. 
Step 1
A compound 4 of Scheme 20 may be first reductively aminated as described in Step 5 of Scheme 1.
Step 2
The optionally esterified ester of the product is hydrolyzed, e.g. by reaction with an alkali hydroxide in a suitable solvent such as aqueous alcohol at from room temperature to reflux.
Step 3
The product is cyclized by standard amide bond forming conditions, e.g. by reaction with BOP in an inert solvent such as DMF in the presence of an optional base such as diisopropylethylamine at about room temperature. 
A compound 2 of Scheme 12 may be directly deprotected as described in Step 3 of Scheme 12 and reacted as described in Step 4 of Scheme 12. Alternatively, a compound 5 of Scheme 12 may be prepared by reduction, e.g. with lithium aluminum hydride or borane, of a compound 3 of Scheme 23, where Z1 does not equal CO. 
A compound 5 of Scheme 1 may be reacted with an imidazole containing aldehyde and an alkali cyanide such as NaCN in the presence of an acid such as acetic acid in a suitable solvent such as methanol/acetonitrile at about room temperature to form a compound 2. The compound 2 may be reduced, e.g. with lithium aluminum hydride, in a suitable solvent such as ether at about room temperature to form a compound 3. The compound 3 wherein R1 is halogen, e.g. bromine, may be prepared from the compound 3 wherein R1=H by reaction with a halogenating agent, e.g. tetrabutylammonium perbromide, in an inert solvent such as chloroform at about room temperature. The compound 3 may be reductively aminated under standard conditions to form the compound 4. 
In step 1 of Scheme 25, an N-(2-nitroaryl)-amino acid ester, available by reaction of an amino acid with a 1-fluoro-2-nitrobenzene followed by esterification, is reduced, e.g. with hydrogen and a palladium catalyst in a suitable solvent such as ethyl acetate at about room temperature. The resulting amine is cyclized to a compound 2 under the reduction conditions. The compound 2 is acylated or sulfonylated as described in Step 4 of Scheme 1. The compound 3 is reduced, e.g. with borane in a suitable solvent such as methanol at about room temperature. The compound 3 wherein R1 is halogen, e.g. bromine, may be prepared from the compound 3 wherein R1=H by reaction with a halogenating agent, e.g. tetrabutylammonium perbromide, in an inert solvent such as chloroform at about room temperature. The compound 4 undergoes reductive amination with an imidazole containing aldehyde as described in Step 5 of Scheme 1. 
In step 1 of Scheme 26, the compound 1 is reacted with a methylenating agent such as N,N,Nxe2x80x2Nxe2x80x2-tetramethyl-diaminomethane in a suitable solvent such as acetic anhydride and DMF at about room temperature. Thereafter, the compound 2 is reacted with a 1,2-phenylenediamine in a suitable solvent such as toluene at about 115xc2x0 C. under dehydrating conditions, e.g. with a Dean-Stark trap, in the presence of a hydroquinone. Thereafter, the compound 3 is both reduced and reductively aminated as described in Step 5 of Scheme 1.